The underlying concept for the synthesis of carbocyclic nucleosides (carbanucleosides) is to generate a stable C-N bond resistant to chemical and enzymatic hydrolysis. However, the absence of the 4'-oxygen (4'O) represents a dramatic change in terms of stereoelectronic effects, and the structural changes ensuing its removal are quite significant. In carbanucleosides, the anomeric effect, as well as important gauche interactions between the 4'O and any electronegative substituents at positions 2' and 3' are abolished. Normally, the combined effect of these interactions drives the conformation of the sugar ring of nucleosides into two preferred forms of puckering: 1) a North conformation approximating a 2'-exo envelope pucker, and 2) a South conformation neighboring a 3'-exo form. In solution, the conformation of a nucleoside is represented by an equilibrium between these two extremes, and the direction of this equilibrium is often determined by the interplay of the above-mentioned forces. In the solid state, however, generally only one of the two typical solution conformations is present, and its selection is usually determined by specific crystal packing forces. Similarly, when a nucleoside or nucleotide binds to its target enzyme, only one form is present in the drug-receptor complex. Carbanucleosides constructed on a bicyclo[3.1.0]hexane template are absolutely rigid and have conformations that mimic the 2'-exo and 3'-exo conformations of conventional nucleosides. We have demonstrated the rigidity and nucleoside mimicry of these carbanucleosides by X-ray analysis and by proton NMR (NOE experiments). This allowed us to begin probing the preference of various important target enzymes by using carbanucleosides having one of the two "fixed" natural nucleoside conformations. As an illustration, we have demonstrated that AZT- triphosphate binds to reverse transcriptase (RT) with a 2'-exo conformation, since only the corresponding 2'-exo rigid carba AZT- triphosphate inhibited RT with the same potency as AZT-triphosphate. Other enzymes, including adenosine deaminase, dTMP kinase, S- adenosylhomocysteine hydrolase, etc. will be probed. Also, the already initiated incorporation of these units into oligodeoxynucleotides (ODNs) will help us evaluate their effect on the macromolecular conformation of the ODNs. AIDS title: Antiherpetic and Anti-HCMV Compounds for the Adjuvant Treatment of AIDS